2-Acyloxy-4-(6-substituted-2-naphthyl)butanes

ABSTRACT

Anti-inflammatory naphthyl compounds, their preparation and pharmaceutical compositions containing the same. The anti-inflammatory activity has a wide spectrum coupled with low side effects such as gastrointestinal irritancy or oestrongenicity. The compounds possess a chiral center at C-2 and can exist as mixtures of optical isomers or as substantially pure optical isomers.

CROSS-REFERENCE

This is a continuation, of Ser. No. 792,724 filed May 2, 1977 nowabandoned.

The present invention provides naphthyl derivatives, a process for theirpreparation and compositions containing them.

Belgian Pat. No. 219794 and British Pat. No. 1474377 disclose inter aliathe compounds of the formula (I): ##STR1## wherein X is CO or CHOH; R isH or CH₃ ; R₁ is a chlorine or bromine atom or a methoxyl, methylthio orC₁₋₄ alkyl group; and the dotted line represents an optional doublebond. The compounds were stated to have a good degree ofanti-inflammatory activity. A distinct group of novel naphthyl compoundshas now been found which have a broad spectrum of anti-inflammatoryactivity coupled with a low level of such side effects as gastrointestinal irritancy or oestrogenicity.

The present invention provides the compounds of the formula (II):##STR2## wherein R₁ is a chlorine or bromine atom or a methoxyl,methylthio or C₁₋₄ alkyl group; n is 1 or 2; the dotted line representsa double bond optionally present; and R₂ is an organic group such thatR₂ CO₂ H is a pharmaceutically acceptable acid of up to 12 carbon atoms.

One suitable group of the compounds of the formula (II) is that of theformula (III) wherein R₁ and R₂ are defined as in relation to formula(II) but a more suitable group of compounds owing to their greaterfreedom from side effects is that of the formula (IV) wherein R₁ and R₂are as defined in relation to formula (II): ##STR3##

Particularly suitable values for R₁ in the compounds of the formulae(II), (III) and (IV) include the chlorine atom and the methyl, methoxyand methylthio groups.

A preferred value for R₁ in the compounds of the formulae (II), (III)and (IV) is the methoxyl group.

Particularly favoured compounds of this invention include those of theformula (IV) wherein R₁ is a methoxyl group.

Suitably R₂ is a hydrocarbon group such as an alkyl, alkenyl, aryl,aralkyl or like group optionally substituted by alkoxyl, carboxyl,carboxamido, hydroxyl, acyloxy, amino, or salted amino, acylamino,alkylamino, dialkylamino or the like. More suitably R₂ is such a groupwhich contains up to 8 carbon atoms.

Preferred groups R₂ include the phenyl group, alkyl groups of 1-4 carbonatoms, alkyl group of 1-4 carbon atoms substituted by a phenyl group, orone of these groups substituted by hydroxyl, acetoxyl, methoxyl,acetamido, amino, salted amino, lower alkylamino, dilower alkylamino,carboxyl or the like groups.

Particularly suitable groups R₂ include the methyl, ethyl, n-propyl,iso-propyl, n-butyl, t-butyl, phenyl, benzyl, phenylethyl,acetoxymethyl, methoxymethyl, hydroxymethyl, aminomethyl,2-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3,4,5-trimethoxyphenyl or the like groups.

Preferred groups R₂ include the methyl, ethyl, benzyl, 2-methoxyethyl,phenyl, 4-methoxyphenyl, salted aminomethyl and the like andparticularly the methyl, ethyl, phenyl, or like groups such as2-acetoxyphenyl.

The compounds of the formulae (II), (III) and (IV) possess a chiralcentre at C-2. The compounds of this invention are envisaged as mixturesof optical isomers and in the form of substantially pure opticalisomers. The S-isomers of the compounds of the formulae (II), (III) and(IV) form a favoured aspect of this invention especially the S-isomersof the compounds of the formula (IV) wherein R₁ is a methoxyl groupsince the relevant intermediates are readily available by the processesdescribed herein.

The present invention also provides a pharmaceutical composition whichcomprises a compound of the invention together with a pharmaceuticallyacceptable carrier.

Most suitably the compositions of this invention are adapted for oraladministration although compositions adapted for other modes ofadministration, such as injection, are also envisaged.

The compositions of this invention may contain conventional carrierssuch as disintegrants, lubricants, binders, flavours or any otherconventional excipient such as those known to be useful in formulatingsuch conventional anti-inflammatory agents as naproxen, ketoprofen,acetylsalicylic acid, indomethacin or the like.

In general the compositions of this invention are provided in unitdosage forms such as tablets, capsules, sachets and their equivalents.Unit dosage compositions will normally contain from 25 mg to 500 mg ofactive agent, and more usually from 50 mg to 250 mgs of active agent.Such compositions may be taken one or more times a day, usually 1 to 6times daily and more usually 2, 3 or 4 times a day. The daily dosage ofactive agent will normally be in the range 200 mg to 1200 mgs for a 70kg adult.

The present invention also provides a process for the preparation of thecompounds of the formula (II) which process comprises the reaction of acompound of the formula (V): ##STR4## wherein R₁ and the dotted line areas defined in relation to formula (II); with a compound of the formula(VI):

    R.sub.2.O.sub.n C.OH                                       (VI)

or a reactive acylating derivative thereof wherein R₂ and n are asdefined in relation to formula (II).

Suitable reactive acylating derivatives of the acid of the formula (VI)include acid halides such as the acid chloride, acid anhydrides, mixedanhydrides, active esters or other conventional acylating agents such asthe derivatives formed by the reaction of the acid (VI) with adehydrating agent such as dicyclohexylcarbodiimide.

If the group R₂ contains an acylatable group such as an amino orhydroxyl group then it should be protected during the reaction inconventional manner for example by protonation or silylation or thelike.

The acylation will normally be carried out in a conventional organicsolvent such as tetrahydrofuran, dioxane, methylene chloride,chloroform, pyridine or toluene. If a non-basic solvent is employed thenan acid acceptor such as pyridine, triethylamine or the like should bepresent during the reaction.

The acylation reaction will normally be carried out at a non-extremetemperature, for example -10° to 100° C. and more usually at about0°-25° C. It is frequently very convenient to carry out the reaction atambient temperature.

If the compound of the formula (V) is a mixture of isomers then thecompound of the formula (II) prepared by this process will normally beproduced as a mixture of isomers. Similarly if the compound of theformula (V) employed is in the form of a pure optical isomer such as theS-isomer than the compound of the formula (II) produced by the processwill also be in the form of the pure optical isomer such as theS-isomer.

The novel S-isomers of the formula (V) are useful intermediates and assuch form a part of this invention. Most suitably such S-isomers of thecompounds of the formula (V) are those wherein the dotted line does notrepresent a double bond.

EXAMPLE 1 2-Acetoxy-4-(6-methoxy-2-naphthyl)butane ##STR5##

To a solution of 4-(6-methoxy-2-naphthyl)-butan-2-ol (1.5 g; 0.005 mole)in dry pyridine was added acetyl chloride (1.4 g; 0.02 mole) dropwise at0° C. The resulting solution solidified and a little dry benzene wasadded and the solution left stirring overnight.

The solution was poured into water and extracted into benzene, dried andevaporated.

The resulting oil was passed down an alumina column and eluted with60°-80° petrol/ether and the pure acetyl compound was obtained in about85% yield as a colourless oil. Analysis: C₁₇ H₂₀ O₃ (Requires C=74.97,H7.40) Found C=74.97, H=7.43

The butanol was prepared as follows:

To a stirred solution of 4-(6'-methoxy-2'-naphthyl)butan-2-one (5 g) inethanol (500 ml) at 5° C. was added sodium borohydride (1 g)portionwise.After a further 3 hours at room temperature the mixture was treatedcarefully with aqueous ammonium chloride, concentrated and extractedseveral times with diethyl ether. The organic extract was washed withwater, dried (Na₂ SO₄) and concentrated to give4-(6-methoxy-2-naphthyl)butan-2-ol, m.p. 94°-5° C. (4.7 g).2-Acetoxy-4-(6-methoxy-2-naphthyl)butane has been shown to be active onthe rat carageenin model at 45 mg/kg per oral and active on the ratcotton pellet test at 50 mg/kg per oral indicating that the compound hasgood anti-inflammatory activity. No gastric irritation has been observedat doses up to 100 mg/kg per os and no deaths in test animals have beenobserved during testing.

EXAMPLE 2 2-Acetoxy-4-(6-methoxy-2-naphthyl)but-3-ene ##STR6##

In a similar manner to Example 1, reduction of4-(6-methoxy-2-naphthyl)but-3-en-2-one with sodium borohydride inethanol gave 4-(6-methoxy-2-naphthyl)but-3-en-2-ol, m.p. 123°-5° C.,which was acetylated as in Example 1 to give2-acetoxy-4-(6-methoxy-2-naphthyl)-but-3-ene, m.p. 78°-80° C.

The above compound was found to be active on the rat cotton pellet testat 50 mg/kg.

EXAMPLE 3 Hydrogen 3,3-dimethylglutarate of2-hydroxy-4-(6-methoxy-2-naphthyl)butane ##STR7##

A mixture of 2-hydroxy-4-(6-methoxy-2-naphthyl)butane (2.3 g: 0.01mole), 3,3-dimethyl glutaric anhydride (1.56 g: 0.011 mole), pyridine (3ml) and toluene (50 ml) was refluxed for 48 hours. The resultingsolution was concentrated, partitioned between ether and water and theorganic layer extracted with dilute aqueous sodium hydroxide. Theseextracts were washed with ether and acidified with dilute hydrochloricacid. The solid which precipitated was collected by filtration andrecrystallised from chloroform/hexane to afford the hydrogen3,3-dimethylglutarate of 2-hydroxy-4-(6'-methoxy-2'-naphthyl)butane,m.p. 85°-6° (2 g).

EXAMPLE 4 3,4,5-Trimethoxybenzoate of2-hydroxy-4-(6-methoxy-2-naphthyl)butane ##STR8##

To a stirred mixture of 2-hydroxy-4-(6-methoxy-2-naphthyl)butane (1.15g: 0.005 mole) in toluene (45 ml) containing dry pyridine (3 ml) wasadded 3,4,5-trimethoxy-benzoyl chloride, prepared from the correspondingacid (1.06 g: 0.005 mole) and oxalyl chloride (1 ml). After standing for48 hours at room temperature, the resulting mixture was added to waterand extracted with ether. The organic extract was washed twice withwater, dried (Na₂ SO₄) and concentrated. The crude oil waschromatographed on alumina (100 g) using 10% ethereal hexane as eluantto afford the 3,4,5-trimethoxybenzoate of2-hydroxy-4-(6-methoxy-2-naphthyl)butane as a pale yellow oil

EXAMPLE 5 S-2-Acetoxy-4-(6-methoxy-2-naphthyl)butane ##STR9##

This was prepared in a similar manner to Example 1 usingS(+)-4-(6-methoxy-2-naphthyl)-butan-2-ol as starting material.

The colourless oil, which was obtained by chromatography as before,solidified on standing. Recrystallisation of this solid gaveS(-)-2-acetoxy-4-(6-methoxy-2-naphthyl)butane, m.p. 41°-3° ; α_(D) ²⁰.0=-16.2 (chloroform).

The above compound was active on the rat carageenin test at 45 mg/kg peros.

EXAMPLE 6 S(+)-2-Hydroxy-4-(6-methoxy-2-naphthyl)butane ##STR10##

To a stirred mixture of 6-methoxy-2-naphthaldehyde (9.3 g: 0.05 mole)and 1,3-propanedithiol (5.1 ml: 0.05 mole) in methylene chloride (50 ml)was added dry HCl gas until the solution became saturated.

Stirring was maintained for a further 1 hour and the resulting slurrypartitioned between water and methylene chloride. The organic layer waswashed successively with water, 1 N potassium hydroxide solution andwater, dried (Na₂ SO₄) and concentrated. Recrystallisation of theresulting solid from methanol gave 2-(6-methoxy-2-naphthyl)-1,3-dithianeas colourless needles, m.p. 190° (11.7 g: 95%).

To a solution of the latter 9.3 g: 0.038 mole) in tetrahydrofuran (250ml) at -40° was added dropwise ethereal butyl lithium (25.2 ml of 16 M:0.038 mole) followed by S(-)-propylene oxide (2.67 ml: 0.038 mole) andthe resulting solution then left overnight at room temperature. Afteracidification with dilute hydrochloric acid the mixture was concentratedand extracted with chloroform. The organic layer was washed with water,dried (Na₂ SO₄) and concentrated to give2-(6-methoxy-2-naphthyl)-2-hydroxypropyl-1,3-dithiane in crudequantitative yield.

This crude dithiane was refluxed for 3 hours with Raney nickel (200 g)in ethanol (500 ml). After filtration through Kieselguhr andconcentration the crude product (7.3 g) was chromatographed on alumina(400 g) using chloroform. Recrystallisation of the resulting solid fromether gave S(+)-2-hydroxy-4-(6-methoxy-2-naphthyl)butane, m.p. 94°-5°;α_(D) ²⁶.2 =12.04° (chloroform).

What we claim is:
 1. A compound of the formula: ##STR11## wherein R₁ ischloro or methoxy andR₂ is methyl, ethyl, benzyl, 2-methoxyethyl,phenyl, 4-methoxyphenyl or aminomethyl.
 2. A compound according to claim1 wherein R₂ is methyl or ethyl.
 3. A compound according to claim 1wherein R₁ is chloro.
 4. A compound according to claim 1 wherein R₁ ismethoxy.
 5. A compound according to claim 1 wherein R₁ is chloro and R₂is methyl.